Creatine, its derivatives, compositions and methods of use thereof

ABSTRACT

The application describes creatine or its derivatives, compositions comprising the same, and uses thereof for topical or systemic administration to treat pain, itch, or eczema, or inflammation associated with a cosmetic or medical condition, disorder or disease in a human subject, wherein the inflammation causes the pain, itch, or eczema. In addition, the application describes clinical use of these compounds and compositions which can reduce or eliminate erythema, edema and tissue distortions associated with inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119 to U.S.Provisional Patent Application No. 63/169,584, filed on April 1, 2021,and U.S Provisional Patent Application No. 63/241,130, filed on Sep. 7,2021, the disclosures of which are herein incorporated by reference intheir entireties.

FIELD OF THE INVENTION

The application describes creatine or its derivatives, compositionscomprising the same, and uses thereof for topical or systemicadministration to treat pain, itch, or eczema, or inflammationassociated with a cosmetic or medical condition, disorder or disease ina human subject. In addition, the application describes clinical use ofthese compounds and compositions which can reduce or eliminate erythema,edema and tissue distortions associated with inflammation.

BACKGROUND OF THE INVENTION

Creatine is thought to improve strength, increase lean muscle mass, andhelp the muscles recover more quickly during exercise. This muscularboost may help athletes achieve bursts of speed and energy, especiallyduring short bouts of high-intensity activities such as weight liftingor sprinting. Creatine is N-methyl-N-guanylglycine, and has thefollowing chemical formula (1):

H₂NC(═NH)N(CH₃)CH₂COOH   Formula (1)

Creatine has a molecular weight of 131. One gram of creatine monohydratedissolves in 75 ml water, about 1.3%, and partially insoluble in alcoholor ether.

US2002/0161049 A1, published on Oct. 31, 2002 by Rima Kaddurah-Daouk etal. and entitled “Use of creatine or creatine analogs for the treatmentof diseases of the nervous system,” US2004/0102419 A1, published on May27, 2004 by Rima Kaddurah-Daouk et al. and entitled “Use of creatine orcreatine analogs for the treatment of diseases of the nervous system,”and US2010/0303840 A1, published Dec. 2, 2010 by Rima Kaddurah-Daouk etal. and entitled

“Use of creatine or creatine analogs for the treatment of diseases ofthe nervous system,” describe the use of creatine, creatine phosphate oranalogs of creatine, such as cyclocreatine, for treating diseases of thenervous system including diabetes, toxic neuropathies, Alzheimer'sdisease, Parkinson's disease, Huntington's, amyotropic lateral sclerosisand multiple sclerosis.

US2005/0227996 A1, published Oct. 13, 2005 by Rima Kaddurah-Daouk et al.and entitled “Use of creatine or creatine compounds for skinpreservation,” describes creatine compounds as energy generatingsystems, antioxidants for preservation of skin against adverse agingeffects.

However, none of the prior art described the use of creatine derivativesof the current invention and compositions thereof to alleviate oreliminate pain, itch, eczema, or inflammation.

BRIEF SUMMARY OF THE INVENTION

The inventors have discovered that creatine or its derivative, with orwithout other pharmacological agents, is cosmetically or therapeuticallyeffective for treating pain, itch, eczema, or discomfort associated withan inflammatory cosmetic or medical condition, disorder, or disease whenadministered topically or systemically to a human subject. Morespecifically, the inventors discovered that creatine or its derivativeis therapeutically effective as an analgesic substance for eradicatingpain, itch, or eczema associated with inflammatory neuropathic pain,itch, eczema, arthritis, migraine headache, acute common headache,osteoarthritis, psoriatic arthritis, rheumatoid arthritis, and variousother pain, itch, or eczemas associated with inflammation in humansubjects, when topically or systemically administered. The inventorshave discovered and repeatedly confirmed that creatine or its derivativeis therapeutically effective for topical or systemic administration toalleviate or eradicate pain, itch, or eczema associated with aninflammatory medical condition, disorder or disease in a human subject.The systemic administration includes parenteral injections, oral ornasal spray, and under the tongue administration (i.e., sublingual), tobypass liver digestion with oral administration.

In one general aspect, the present application relates to creatine or aderivative thereof of Formula (2):

H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2)

or a pharmaceutically acceptable salt thereof or a solvate thereof,

wherein, R₁ is H or an acyl radical having up to 29 carbon atoms; R₂ isH, OR₃, NHR₄, or any other amino group containing radical having up to10 carbon atoms; R₃ is H, an alkyl, aralkyl or aryl radical, wherein thealkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R₄ is H,OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl,aryl or acyl radical has up to 19 carbon atoms.

In some embodiments, R₂ is H, OR₃, or NHR₄, preferably H, OH, OEt,OC₃H₇, NHOH, or NH₂.

In some embodiments, R₂ is NHNHR₅; and R₅ is H, OH, an alkyl, aralkyl,aryl or acyl radical, wherein the alkyl, arakyl, aryl, or acyl radicalhas up to 19 carbon atoms.

In some embodiments, R₂ is NHNH₂, NHNHAc, NHCONH₂, NH(C═NH)NH₂,NH(C═NH)NHNH_(2,)NHNH(C═NH)NH₂, NH(C═NH)NHNHAc, NHNH(C═NH)NHAc, or(H₃C)₂N(C═N)N(CH₃)₂.

In another general aspect, the present application relates to acomposition comprising creatine or a derivative thereof of Formula (2):

H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2)

or a pharmaceutically acceptable salt thereof or a solvate thereof, andoptionally a pharmaceutically or cosmetically acceptable carrier,

wherein, R₁ is H or an acyl radical having up to 29 carbon atoms; R₂ isH, OR₃, NHR₄, or any other amino group containing radical having up to10 carbon atoms; R₃ is H, an alkyl, aralkyl or aryl radical, wherein thealkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R₄ is H,OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl,aryl or acyl radical has up to 19 carbon atoms.

In some embodiments, the composition is for topical administration.

In some embodiments, the composition is for systemic administration,including subcutaneous injection.

In some embodiments, the composition is used to alleviate pain, itch, oreczema, or inflammation in a human subject in need thereof.

In particular embodiments, the pain, itch, or eczema is associated witha medical condition, disorder or disease including arthritis (e.g.,osteoarthritis, psoriatic arthritis, etc.), headache (e.g., migraineheadache, hangover headache, etc.), dental pain, itch, eczema, lipoma,muscle pain, itch, eczema, pharyngitis, sprain, trauma, sunburn, andthermal burns.

In yet another general aspect, the present application relates to amethod for treating pain, itch, or eczema, or inflammation in a humansubject in need thereof, the method comprising administering to thehuman subject a composition comprising creatine or a derivative thereofof Formula (2):

H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2)

or a pharmaceutically acceptable salt thereof or a solvate thereof, andoptionally a pharmaceutically or cosmetically acceptable carrier,

wherein, R₁ is H or an acyl radical having up to 29 carbon atoms; R₂ isH, OR₃, NHR₄, or any other amino group containing radical having up to10 carbon atoms; R₃ is H, an alkyl, aralkyl or aryl radical, wherein thealkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R₄ is H,OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl,aryl or acyl radical has up to 19 carbon atoms.

In some embodiments, the composition is administered topically.

In some embodiments, the composition is administered systemically,including by subcutaneous injection.

In some embodiment, the method is for treating pain in the humansubject.

In particular embodiments, the pain is associated with a medicalcondition, disorder or disease including arthritis (e.g.,osteoarthritis, psoriatic arthritis, etc.), headache (e.g., migraineheadache, hangover headache, etc.), dental pain, itch, eczema, lipoma,muscle pain, pharyngitis, sprain, trauma, sunburn, and thermal burns.

Other aspects, features and advantages of the invention will be apparentfrom the following disclosure, including the detailed description of theinvention and its preferred embodiments, and the appended claims.

DESCRIPTION OF THE INVENTION

Various publications, articles and patents are cited or described in thebackground and throughout the specification; each of these references isherein incorporated by reference in its entirety. Discussion ofdocuments, acts, materials, devices, articles or the like which has beenincluded in the present specification is for the purpose of providingcontext for the present invention.

Such discussion is not an admission that any or all of these mattersform part of the prior art with respect to any inventions disclosed orclaimed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Otherwise, certain terms usedherein have the meanings as set forth in the specification. All patents,published patent applications and publications cited herein areincorporated by reference as if set forth fully herein.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural reference unless thecontext clearly dictates otherwise.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integer or step. Whenused herein the term “comprising” can be substituted with the term“containing” or “including” or sometimes when used herein with the term“having”.

When used herein “consisting of” excludes any element, step, oringredient not specified in the claim element. When used herein,“consisting essentially of” does not exclude materials or steps that donot materially affect the basic and novel characteristics of the claim.Any of the aforementioned terms of “comprising”, “containing”,“including”, and “having”, whenever used herein in the context of anaspect or embodiment of the invention can be replaced with the term“consisting of” or “consisting essentially of” to vary scopes of thedisclosure.

As used herein, the term “treatment” or “treating” refers toamelioration, improvement, prophylaxis, or reversal of a disease ordisorder, or at least one discernible symptom thereof. In certainembodiment, “treatment” or “treating” refers to amelioration,improvement, prophylaxis, or reversal of at least one measurablephysical parameter related to the disease or disorder being treated, notnecessarily discernible in or by the mamma! or subject. In anotherembodiment, “treatment” or “treating” refers to inhibiting or slowingthe progression of a disease or disorder, either physically, e.g.,stabilization of a discernible symptom, physiologically, e.g.,stabilization of a physical parameter, or both. In yet anotherembodiment, “treatment” or “treating” refers to delaying the onset of adisease or disorder,

In some embodiments, compounds and composition as described in thepresent application are administered as a preventative measure. As usedherein, “prevention” or “preventing” refers to a reduction of the riskof acquiring a given disease or disorder.

Common or certain knowledge, scientific and medical terminologies can bereadily found via internet, textbooks of chemistry, biochemistry,medicinal chemistry, pharmacology, dermatology and general medicine. Thefollowing are some examples. Robert K. Murray et al. eds. “Harper'sIllustrated Biochemistry” 26th ed. Vol. I-II, McGraw Hill, 2003.Laurence L. Brunton et al. eds.

“Goodman & Gilman's The Pharmacological Basis of Therapeutics” 12th ed.McGraw Hill Medical, 2011. Anthony S. Fauci et al. eds. “Harrison'sPrinciples of Internal Medicine” 17^(th) ed., McGraw Hill Medical, NewYork, 2008. Abba J. Kastin, Ed “Handbook of Biologically ActivePeptides” 2n^(d) ed .Academic Press, 2013. John Howl and Sarah Jones Ed“Bioactive peptides”, CRC Press 2009.

Certain abbreviations and terms used herein include: Ac (acetyl), Ba(butanoyl), Bo (benzyloxycarbonyl), Bz (benzoyl), Fo (formyl), Hd(hexadecanoyl), He (hexanoyl), Hp (heptanoyl), Le (linoleic), Ln(linolenic), Na (nonanoyl), Oa (octanoyl), Pa (propanoyl), Pc(phenylacetyl), Pe (pentanoyl), Pg (pyroglutamyl); ethyl ester, OEt;propyl ester, OPr; and methyl ester, OMe; —NH(C═NH)NHNH₂, aminoguanidineradical; —NHNH(C═NH)NH₂, aminoguanidine radical with differentattachment.

In one general aspect, the present application relates to creatine or aderivative thereof of Formula (2):

H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2)

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, R₁ is H or an acyl radical having up to 29 carbon atoms; R₂ isH, OR₃, NHR₄, or any other amino group containing radical having up to10 carbon atoms; R₃ is H, an alkyl, aralkyl or aryl radical, wherein thealkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R₄ is H,OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl,aryl or acyl radical has up to 19 carbon atoms.

A typical acyl radical and abbreviation suitable for use in theinvention includes, but is not limited to, Ac (acetyl), Ba (butanoyl),Bo (benzyloxycarbonyl), Bz (benzoyl), Fo (formyl), Hd (hexadecanoyl), He(hexanoyl), Hp (heptanoyl), Le (linoleic), Ln (linolenic), Na(nonanoyl), Oa (octanoyl), Pa (propanoyl), Pc (phenylacetyl), Pe(pentanoyl), and Pg (pyroglutamyl).

In some embodiments, R₁ is H, Ac (acetyl), Ba (butanoyl), Bo(benzyloxycarbonyl), Bz (benzoyl), Fo (formyl), Hd (hexadecanoyl), He(hexanoyl), Hp (heptanoyl), Le (linoleic), Ln (linolenic), Na(nonanoyl), Oa (octanoyl), Pa (propanoyl), Pc (phenylacetyl), Pe(pentanoyl), or Pg (pyroglutamyl).

In some embodiments, R₁ is H, Ac (acetyl), Bz (benzoyl), or Pc(phenylacetyl).

In some embodiments, R₂ is H, OR₃, or NHR₄, preferably H, OH, OEt,OC₃H₇, NHOH, or NH₂.

In some embodiments, R₂ is NHNHR₅; and R₅ is H, OH, an alkyl, aralkyl,aryl or acyl radical, wherein the alkyl, arakyl, aryl, or acyl radicalhas up to 19 carbon atoms.

In some embodiments, R₂ is NHNH₂, NHNHAc, NHCONH₂, NH(C═NH)NH₂,NH(C═NH)NHNH₂, NHNH(C═NH)NH₂, NH(C═NH)NHNHAc, NHNH(C═NH)NHAc, or(H₃C)₂N(C═N)N(CH₃)₂.

In certain embodiments, R₂ is NH(C═NH)NH₂, NH(C═NH)NHNH₂, orNHNH(C═NH)NH₂.

Representative creatine or the derivatives in Formula (2) are listed inTable 1:

TABLE 1 Representative Compounds Compound No. Compound Name StructureC10 creatine H₂NC(═NH)N(CH₃)CH₂COOH C11 creatinamideH₂NC(═NH)N(CH₃)CH₂CONH₂ C12 ethyl creatinate H₂NC(═NH)N(CH₃)CH₂COOC₂H₅C13 N-acetyl creatine H₂NC(═NAc)N(CH₃)CH₂COOH C14 N-acetyl creatinamideH₂NC(═NAc)N(CH₃)CH₂CONH₂ C15 N-acetyl ethyl creatinateH₂NC(═NAc)N(CH₃)CH₂COOC₂H₅ C16 creatine aldehyde H₂NC(═NH)N(CH₃)CH₂CHOC17 N-acetylcreatine aldehyde H₂NC(═NAc)N(CH₃)CH₂CHO C18 N-benzoylcreatine H₂NC(═NBz)N(CH₃)CH₂COOH C19 N-benzoyl creatinamide H₂NC(═NBz)N(CH₃)CH₂CONH₂ C20 N-benzoyl ethyl creatinateH₂NC(═NBz)N(CH₃)CH₂COOC₂H₅ C21 N-benzoyl creatine aldehydeH₂NC(═NBz)N(CH₃)CH₂CHO C22 creatinoylguanidineH₂NC(═NH)N(CH₃)CH₂CONH(C═NH)NH₂ C23 N-acetylcreatinoylguanidineH₂NC(═NAc)N(CH₃)CH₂CONH(C═NH)NH₂ C24 creatinylaminoguanidineH₂NC(═NH)N(CH₃)CH₂CONHNH(C═NH)NH₂ C25 N-acetylcreatinylamino-H₂NC(═NAc)N(CH₃)CH₂CONHNH(C═NH)NH₂ guanidine C26 N-2-acetoxybenzoylethyl H₂NC(═NAb)N(CH₃)CH₂COOC₂H₅ creatinate C27 N-2-acetoxybenzoylcreatine H₂NC(═NAb)N(CH₃)CH₂COOH C28 N-2-acetoxybenzoylH₂NC(═NAb)N(CH₃)CH₂CONH₂ creatinamide C29 N-acetyl propyl creatinateH₂NC(═NAc)N(CH₃)CH₂COOC₃H₇ C30 N-2-acetoxybenzoyl propylH₂NC(═NAb)N(CH₃)CH₂COOC₃H₇ creatinate C31 N-phenylacetyl creatineH₂NC(═NPc)N(CH₃)CH₂COOH Note: Ac: acetyl; Ab: acetoxybenzoyl; Bz:benzoyl; Pc: Phenylacetyl; Guanidine: —NH(C═NH)NH₂; Aminoguanidine:—NHNH(C═NH)NH₂ or —NH(C═NH)NHNH₂.

The phrase “pharmaceutically acceptable salt”, as used herein, meansthose salts of a compound of interest that are safe and effective foruse in mammals and that possess the desired biological activity.Pharmaceutically acceptable salts include salts of acidic or basicgroups present in the specified compounds. Pharmaceutically acceptableacid addition salts include, but are not limited to, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, carbonate, bicarbonate, acetate, lactate,salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate,malonate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compoundsused in the application can form pharmaceutically acceptable salts withvarious amino acids. Suitable base salts include, but are not limitedto, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc,bismuth, and diethanolamine salts. For a review on pharmaceuticallyacceptable salts see Berge et al., 66 J. Pharm. Sci. 1-19 (1977),incorporated herein by reference.

Compounds of the present application can exist in solvated andunsolvated forms. The term “solvate,” as used herein, means a physicalassociation, e.g., by hydrogen bonding, of a compound of the applicationwith one or more solvent molecules. The solvent molecules in the solvatecan be present in a regular arrangement and/or a non-orderedarrangement. The solvate can comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Compounds of the applicationcan form solvates with water (i.e., hydrates) or common organicsolvents. Exemplary solvates include, but are not limited to, hydrates,ethanolates, methanolates, and isopropanolates. Methods of solvation aregenerally known in the art.

Compounds of the present application can be made or synthesized by anymethod known to those skilled in the art in view of the presentdisclosure. Methods of making creatine derivatives, such as by chemicalsynthesis, are well known to those of ordinary skill in the art in viewof the present disclosure.

In another general aspect, the present application relates to acomposition comprising creatine or a derivative thereof of Formula (2):

H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2)

or a pharmaceutically acceptable salt thereof or a solvate thereof, andoptionally a pharmaceutically or cosmetically acceptable carrier,

wherein, R₁ is H or an acyl radical having up to 29 carbon atoms; R₂ isH, OR₃, NHR₄, or any other amino group containing radical having up to10 carbon atoms; R₃ is H, an alkyl, aralkyl or aryl radical, wherein thealkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R₄ is H,OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl,aryl or acyl radical has up to 19 carbon atoms. A composition accordingto the invention can comprise creatine or any derivative thereof ofFormula (2) or any pharmaceutically acceptable salt thereof or anysolvate thereof described herein.

In some embodiments, R₁ is H, Ac (acetyl), Ba (butanoyl), Bo(benzyloxycarbonyl), Bz (benzoyl), Fo (formyl), Hd (hexadecanoyl), He(hexanoyl), Hp (heptanoyl), Le (linoleic), Ln (linolenic), Na(nonanoyl), Oa (octanoyl), Pa (propanoyl), Pc (phenylacetyl), Pe(pentanoyl), or Pg (pyroglutamyl).

In some embodiments, R₁ is H, Ac (acetyl), Bz (benzoyl), or Pc(phenylacetyl).

In some embodiments, R₂ is H, OR₃, or NHR₄, preferably H, OH, OEt,OC₃H₇, NHOH, or NH₂.

In some embodiments, R₂ is NHNHR₅; and R₅ is H, OH, an alkyl, aralkyl,aryl or acyl radical, wherein the alkyl, arakyl, aryl, or acyl radicalhas up to 19 carbon atoms.

In some embodiments, R₂ is NHNH₂, NHNHAc, NHCONH₂, NH(C═NH)NH₂,NH(C═NH)NHNH₂, NHNH(C═NH)NH₂, NH(C═NH)NHNHAc, NHNH(C═NH)NHAc, or(H₃C)₂N(C═N)N(CH₃)₂.

In certain embodiments, R₂ is NH(C═NH)NH₂, NH(C═NH)NHNH₂, orNHNH(C═NH)NH₂.

Representative creatine or the derivatives in Formula (2) are listed inTable 1 described above.

In a particular embodiment, the composition comprises N-acetyl ethylcreatinate.

In another particular embodiment, the composition comprises creatinemonohydrate.

In another particular embodiment, the composition comprises HCl salt ofethyl creatinate. According to embodiments of the present application,the composition comprises a therapeutically effective amount of creatineor a derivative thereof of Formula (2) or a pharmaceutically acceptablesalt thereof or a solvate thereof. In view of the present disclosure,standard procedures can be performed to evaluate the effect ofadministration of a composition to a subject (e.g., determine whether aclinically observable beneficial effect is achieved), thus allowing askilled artisan to determine the therapeutically effective amount ofcreatine or the derivative thereof of the pharmaceutically acceptablesalt thereof or the solvate thereof. A clinically observable beneficialeffect can be a situation that, when a composition of the invention isadministered to a subject after symptoms to be treated are observable,the symptoms are prevented from further development or aggravation, ordevelop to a lesser degree than without administration of thecomposition of the invention. The clinically observable beneficialeffect can also be that, when a composition of the invention isadministered to a subject before symptoms to be treated are observable,the symptoms are prevented from occurring or subsequently occur to alesser degree than without administration of the composition.

In some embodiments, a therapeutically effective amount of creatine or aderivative thereof of Formula (2) or a pharmaceutically acceptable saltthereof or a solvate thereof of the invention can alleviate or eliminatepain, itch, eczema or discomfort associated with an inflammatorycosmetic or medical condition, disorder, or disease in a human subjectto be treated or who has been treated, by at least about 20%, forexample, by at least about 30%, by at least about 40%, by at least about50%, by at least about 60%, by at least about 70%, by at least about80%, by at least about 90%, or about 100%, preferably by at least about25%; by at least about 50%, by at least about 75%, or by at least about90% to 100%, relative to the condition or discomfort, associated withpain prior to administration of a composition of the invention. In someembodiments, the composition comprises at least 1% by weight or volume,based on a total weight or volume of the composition, of creatine or aderivative thereof of Formula (2) or a pharmaceutically acceptable saltthereof or a solvate thereof according to the invention. In certainembodiments, a topical composition of the invention comprises about 1%to about 10% by weight or volume, based on a total weight or volume ofthe composition, of creatine or a derivative thereof of Formula (2) or apharmaceutically acceptable salt thereof or a solvate thereof accordingto the invention, such as, about 1%, 1.5% 2%, 2.5%, 3%, 3.5%, 4%, 4.5%,5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%, or any numberin between, by weight or volume.

Compositions of the invention can be formulated for administrationaccording to any method known in the art. Typically, the compositionsare formulated for topical administration or systemic administration.The topical application includes administration to skin, mucousmembranes of the conjunctiva, nasopharynx, oropharynx, vagina, urethra,rectum, and anus. The systemic administration includes oral (enteral)administration and parenteral injections. The parenteral injectionsinclude intravenous injection or infusion, intra-arterial injection,subcutaneous injection, intramuscular injection, and intra-articularinjection. Other routes of administration include sublingualadministration, oral or nasal spray, under the tongue, from oral mucosabypassing the portal circulation, and pulmonary adsorption by inhalingand absorbing through the respiratory tract. In some embodiments, thecomposition is for topical administration.

In some embodiments, the composition is for systemic administration,preferably parenteral injection, more preferably subcutaneous injection.

In some embodiments, the composition is for oral or nasal spray, orsublingual administration.

Compositions according to embodiments of the invention can furthercomprise a pharmaceutically or cosmetically acceptable carrier.Pharmaceutically and cosmetically acceptable carriers are well known tothose of ordinary skill in the art and one of ordinary skill in the artwould be able to select an appropriate pharmaceutical or cosmeticallyacceptable carrier for inclusion in a composition of the inventiondepending on a variety of factors including the type of composition,e.g., solution (aqueous or anhydrous), cream, etc., and intended routeof administration, e.g., topical, systemic, etc., based on generalknowledge in the art in view of the present disclosure.

In some embodiments, a composition of the invention is formulated in anymanner suitable for topical administration to a human subject,preferably for topical application to skin of a human subject. Forexample, for topical application, a composition comprising creatine or aderivative thereof of Formula (2) or a pharmaceutically acceptable saltthereof or a solvate thereof according to the invention can beformulated as a solution, gel, lotion, cream, oil-in-water emulsion,water-in-oil emulsion, ointment, shampoo, spray, stick, powder, mask,pads, mouth rinse or wash, or other form acceptable for use on skin,oral mucosa, mouth or gums.

In some embodiments, a composition of the invention is formulated in anymanner suitable for systemic administration to a human subject,preferably for parenteral injection including subcutaneous injection toa human subject. For parenteral injections, creatine or a derivativethereof of Formula (2) or a pharmaceutically acceptable salt thereof ora solvate thereof is prepared in a solution or suspension understerilized conditions in concentration from about 1% to about 10%, byweight or volume in water, ethanol, propylene glycol, a mixture thereof,or in other vehicle or carrier. The other vehicle or carrier includespeanut oil, soybean oil, mineral oil, sesame oil, and the like.

In some embodiments, the composition further comprises otherpharmacological agents, such as a cosmetic, pharmaceutical or othertopical agent. The cosmetic, pharmaceutical or other topical agent canbe added to the inventive composition for synergetic or synergisticeffect.

According to embodiments of the present application, examples of thetopical agent include, but not limited to, local analgesics andanesthetics, anti-microbial agents, anti-inflammatory agents, anti-agingand anti-wrinkle agents, sunblock and sunscreen agents, vitamins, andcorticosteroids.

In some embodiments the topical agents include, but not limited to:acetaminophen, 2-acetoxybenzoic acid; benzophenone; betamethasonedipropionate; bupivacaine; butoconazole; caffeic acid; caffeine;clobetasol propionate; clotrimazole; dapsone; erythromycin; gluconicacid, gluconolactone, glucuronic acid, glucuronolactone, glycolic acid;hydrocortisone; hydrocortisone 21-acetate, hydrocortisone 17-butyrate,hydrocortisone 17-valerate, hydrogen peroxide; hydroquinone; kojic acid;lactic acid; lidocaine; mandelic acid; minoxidil; retinal;13-cis-retinoic acid; retinoic acid; retinol; retinyl acetate; retinylpalmitate; and triamcinolone acetonide.

In yet general aspect, the present application relates to a method fortreating pain, itch, or eczema, or inflammation in a human subject inneed thereof, the method comprising administering to the human subject acomposition comprising creatine or a derivative thereof of Formula (2):

H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2)

or a pharmaceutically acceptable salt thereof or a solvate thereof, andoptionally a pharmaceutically or cosmetically acceptable carrier,

wherein, R₁ is H or an acyl radical having up to 29 carbon atoms; R₂ isH, OR₃, NHR₄, or any other amino group containing radical having up to10 carbon atoms; R₃ is H, an alkyl, aralkyl or aryl radical, wherein thealkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R₄ is H,OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl,aryl or acyl radical has up to 19 carbon atoms. Any compositiondescribed in the present application can be used in the method.

In some embodiments, R₁ is H, Ac (acetyl), Ba (butanoyl), Bo(benzyloxycarbonyl), Bz (benzoyl), Fo (formyl), Hd (hexadecanoyl), He(hexanoyl), Hp (heptanoyl), Le (linoleic), Ln (linolenic), Na(nonanoyl), Oa (octanoyl), Pa (propanoyl), Pc (phenylacetyl), Pe(pentanoyl), or Pg (pyroglutamyl).

In some embodiments, R₁ is H, Ac (acetyl), Bz (benzoyl), or Pc(phenylacetyl).

In some embodiments, R₂ is H, OR₃, or NHR₄, preferably H, OH, OEt,OC₃H₇, NHOH, or NH₂.

In some embodiments, R₂ is NHNHR₅; and R₅ is H, OH, an alkyl, aralkyl,aryl or acyl radical, wherein the alkyl, arakyl, aryl, or acyl radicalhas up to 19 carbon atoms.

In some embodiments, R₂ is NHNH₂, NHNHAc, NHCONH₂, NH(C═NH)NH₂,NH(C═NH)NHNH₂, NHNH(C═NH)NH₂, NH(C═NH)NHNHAc, NHNH(C═NH)NHAc, or(H₃C)₂N(C═N)N(CH₃)₂.

In certain embodiments, R₂ is NH(C═NH)NH₂, NH(C═NH)NHNH₂, orNHNH(C═NH)NH₂.

Representative creatine or the derivatives in Formula (2) are listed inTable 1 described above.

In a particular embodiment, the composition comprises N-acetyl ethylcreatinate.

In another particular embodiment, the composition comprises creatinemonohydrate.

In another particular embodiment, the composition comprises HCl salt ofethyl creatinate.

In some embodiments, the composition is administered topically.

In some embodiments, the composition is administered systemically,preferably by parenteral injection, more preferably by subcutaneousinjection.

In some embodiments, the composition is administered by oral or nasalspray, or sublingual administration.

According to embodiments of the present application, the methodcomprises administering to the human subject a therapeutically effectiveamount of creatine or a derivative thereof of Formula (2) or apharmaceutically acceptable salt thereof or a solvate thereof accordingto the invention, or a composition comprising the same. Creatine or aderivative thereof of Formula (2) or a pharmaceutically acceptable saltthereof or a solvate thereof, or any composition described herein, issuitable for use in the methods of the invention.

According to embodiments of the of the present application, thecomposition can be administered alone or optionally in combination withanother pharmacological agent. The composition and the otherpharmacological agent can be administered simultaneously or sequentiallyto provide synergetic, synergistic, or enhanced effects. Examples of theother pharmacological agent suitable for use in the methods of theinvention include, but are not limited to, acetaminophen,2-acetoxybenzoic acid; benzophenone; betamethasone dipropionate;

bupivacaine; butoconazole; caffeic acid; caffeine; clobetasolpropionate; clotrimazole; dapsone; erythromycin; gluconic acid,gluconolactone, glucuronic acid, glucuronolactone, glycolic acid;hydrocortisone; hydrocortisone 21-acetate, hydrocortisone 17-butyrate,hydrocortisone 17-valerate, hydrogen peroxide; hydroquinone; kojic acid;lactic acid; lidocaine; mandelic acid; minoxidil; retinal;13-cis-retinoic acid; retinoic acid; retinol; retinyl acetate; retinylpalmitate; and triamcinolone acetonide.

The compounds and compositions according to the invention can provideanalgesic effects, and can thus be used to treat pain, itch, eczema orother discomfort in a human subject. In addition, the compounds andcompositions according to the invention reduce or eliminate erythema,edema and tissue distortions associated with inflammation.

In some embodiments, the method can alleviate or eliminate the pain,itch, eczema or other discomfort in a human subject in a human subject.

In some embodiments, the pain, itch, eczema or other discomfort isassociated with an inflammatory cosmetic or medical condition, disorder,or disease.

In particular embodiments, the pain, itch, eczema or other discomfort isassociated with a medical condition, disorder or disease includingarthritis (e.g., osteoarthritis, psoriatic arthritis, rheumatoidarthritis, etc.), headache (e.g., migraine headache, hangover headache,acute common headache, etc.), dental pain, itch, eczema, lipoma, musclepain, eczema, pharyngitis, sprain, trauma, sunburn, mosquito bites, andthermal burns.

The phrase “associated with,” as used herein with reference to pain,itch, or eczema and any particular disease, disorder, condition, symptomor syndrome, means that the pain, itch, or eczema is caused by thedisease, disorder, condition, syndrome or symptom, or experienced,observed, or perceived by the human subject at substantially the sametime as the occurrence of the disease, disorder, condition, syndrome orsymptom. For example, in one embodiment, “pain associated witharthritis” means that the pain, itch, or eczema in the human subject iscaused by the arthritis. In another embodiment, “pain associated witharthritis” means that the pain, itch, or eczema is experienced,observed, or perceived by the human subject at substantially the sametime as the occurrence of the arthritis in the human subject.

In particular embodiments, the method is for treating pain in the humansubject. In more particular embodiments, the pain is associated with amedical condition, disorder or disease including arthritis (e.g.,osteoarthritis, psoriatic arthritis, rheumatoid arthritis, etc.),headache (e.g., migraine headache, hangover headache, acute commonheadache, etc.), dental pain, itch, eczema, lipoma, muscle pain, eczema,pharyngitis, sprain, trauma, sunburn, mosquito bites, and thermal burns.

Dosages and dosing frequency are determined by a trained medicalprofessional depending on the analgesic effectiveness of creatine or aderivative thereof of Formula (2) or a pharmaceutically acceptable saltthereof or a solvate thereof, or a composition comprising the same thatis used, the characteristics of the particular formulation, and theidentity and severity of pain, itch, eczema or other discomfort treated.One of ordinary skill in the art will be able to determine appropriatetreatment dosage and frequency based on general knowledge in the art inview of the present disclosure. The compound or the compositionaccording to the invention can be administered as often as needed toeliminate or eliminate pain, itch, eczema, or other discomfort.

In view of the present disclosure, standard procedures can be performedto evaluate the analgesic effect of creatine or a derivative thereof ofFormula (2) or a pharmaceutically acceptable salt thereof or a solvatethereof, or a composition comprising the same that is administrated to ahuman subject, thus allowing a skilled artisan to determine thetherapeutically effective amount, the route of administration, thedosing frequency, etc. Because pain, itch_(;) or eczema is a subjectivecondition or symptom based on perception, sensation or reaction, thehuman subject to be treated is preferably able to participate in theevaluation of the therapeutic efficacy of creatine or a derivativethereof of Formula (2) or a pharmaceutically acceptable salt thereof ora solvate thereof, or a composition comprising the same.

For example, clinical evaluation of analgesic effectiveness can bedefined as 1+(25%), which represents partial relief of pain, itch, oreczema for less than 6 hours; 2+- (50%), which represents substantialbut incomplete relief of pain, itch, or eczema for less than 6 hours;3+(75%), which represents complete relief of pain, itch, or eczema forless than 6 hours and 4+(90-100%), which represents complete relief oreradication of pain, itch, or eczema for more than 6 hours. Suchclinical evaluation can be used to determine the analgesic effectivenessof administration (e.g., topical administration or systemicadministration) of creatine or a derivative thereof of Formula (2) or apharmaceutically acceptable salt thereof or a solvate thereof, or acomposition comprising the same,

Based on the clinical findings described herein, topical or systemicadministration of creatine or a derivative thereof of Formula (2) or apharmaceutically acceptable salt thereof or a solvate thereof, or acomposition comprising the same are therapeutically effective fortreating pain, itch, or eczema of arthritis, inflammation, and otherconditions, disorders or syndromes associated with inflammation incancers, infections, and inflammatory disorders of the immune system,nervous system, musculoskeletal system, or other system.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the following Examples, test results andappended claims.

EXAMPLES

The following examples of the invention are to further illustrate thenature of the invention.

It should be understood that the following examples do not limit theinvention and that the scope of the invention is to be determined by theappended claims.

Example 1 Formulation Vehicles

As used in the present application, “WEP 442” represents water 40 parts,ethanol 40 parts and propylene glycol 20 parts by volume; “NEP 433”represents water 40 parts, ethanol 30 parts and propylene glycol 30parts by volume; “WEP 244” represents water 20 parts, ethanol 40 partsand propylene glycol 40 parts by volume; “EP 55” represents an anhydrouscomposition with ethanol 50 parts and propylene glycol 50 parts byvolume; and “WP 82” represents water 80 parts and propylene glycol 20parts by volume.

Example 2 Evaluation of Analgesic Effectiveness

Five scales were used to evaluate the efficacy of analgesic effect: 0(zero) for no effect; 1+(25%), which represents partial relief of pain,itch, or eczema for less than 6 hours; 2+(50%), which representssubstantial but incomplete relief of pain, itch, or eczema for less than6 hours; 3+(75%), which represents complete relief of pain, itch, oreczema for less than 6 hours; and 4+(90-100%), which represents completerelief or eradication of pain, itch, or eczema for more than 6 hours

Example 3 Preparation of Formulation of C12X4WEP442

HCl salt of ethyl creatinate 1 gram was dissolved in 24 ml of a solutionprepared from water 40 parts, ethanol 40 parts and propylene glycol 20parts by volume. L-arginine 0.15 gram was then added to the resultingsolution raise the pH from 2.7 to 5.2. The formulation thus obtainedcontained 4% ethyl creatinate and was referred to as C₁₂X4WEP442.

Example 4 Effects on Osteoarthritis

A female subject, age 68, with worsening osteoarthritis of both knees,who had been advised to have surgical knee replacement, sought advice onpossible alternative treatments. She was provided with the followingformulations for topical applications: Formulation A:

Component Percentage (%) Creatine monohydrate 2 Malic acid 0.1 Sodiumlauryl sulfate 2 Polysorbate 80 0.6 Propylene glycol 3 Mineral oil 0.3Water 92 Final pH 4.6

Formulation B:

Component Percentage (%) Creatine monohydrate 2 Vinegar 4 Sodium laurylsulfate 2 Polysorbate 80 0.6 Propylene glycol 3 Mineral oil 0.4 Water 88Final pH 4.5

Subject reported that the formulation A and formulation B were equallyeffective in providing pain relief, of estimated 80%, within 3-8 minutesafter application to the knees and lasting for 4-5 hours. Pain reliefhas been sufficient for her to postpone consideration of kneereplacement until the COVID-19 pandemic is subdued.

Example 5 Effects on Back Pain

A female subject, age 62, with aggravating lower back pain of 2-3 yearsduration, was provided 8 ounces of Formulation A (Example 4) to beapplied to the lower back in late afternoon when her lower back painintensified from mild to substantial. Pain subsided completely within3-4 minutes, not returning until early afternoon the next day, beginningas mild and worsening during the afternoon hours.

Subject was then instructed to apply the Formulation A to the entirelower back area in late morning, before lower back pain had started orwas of minor degree. When applications were made at this early time, nodisturbing pain or discomfort developed later on. After a test period ofa month subject reported that she had become almost entirely free oflower back pain day after day.

The foregoing events and observations show that creatine appliedtopically can prevent the development of lower back pain as well asalleviate it. The mechanism of these actions is unclear. But theseeffects suggest that topical creatine application can be put topractical clinical therapeutic use.

Example 6 Effects on Psoriatic Arthritis

A female subject, age 60, with worsening psoriatic arthritis over thepast decade, was provided the same Formulation A of the foregoingExample 4. Applications of the formulation as often as needed toaffected joints of left shoulder, both wrists and right ankle providedcomplete relief of pain within 3-5 minutes and lasted for 5-7 hours.

To provide similar complete relief of pain, in multiple finger jointsnitrile gloves containing about 0.2 ml of the formulation in each glovefinger were worn for 10-15 minutes, which provided complete pain relieffor 3-5 hours. Subject needed to repeat the procedure 2-3 times daily tomaintain relief of finger pain. In addition to the relief of fingerpain, swelling (edema) of the arthritic joints became reduced to thedegree that rings for her fingers that could not be worn earlier couldagain be worn.

Example 7 Effects on Osteoarthritis of Fingers, Wrists, Shoulder, Neck

A male subject, age 92, with career as carpenter/builder, who sufferedconsequent osteo-arthritis of fingers, wrists, left shoulder and neck,was provided the same Formulation A of the foregoing Example 4.Applications of the formulation to the sites of pain for an interval of3 weeks relieved pain completely or near completely for 48 hours,including the relief of pain throughout the night, with sleepundisturbed by body movements during sleeping hours. After 2 weeks ofuse pain was relieved for longer and longer periods, i.e. for days.After the last application the fingers and wrists were pain free fornearly a month.

Such effect could be due to a sustained anti-inflammatory action sinceinflammation is the actual cause of pain in numerous disorders.

Example 8 Effect on Post Fracture Acute Ankle Pain

A 50 year old female subject with a history of fractured left ankleseven years earlier, who had worn a plaster cast for several weeks atthat time, related that for the past three months disturbing andincreasing pain in the left ankle, which was occurring daily and wasdisturbing her sleep every night. Oral ibuprofen did relieve the painfor several hours, but the pain always recurred. She was provided 8ounces of the above Formulation A (Example 4), to be applied to thepainful ankle as needed. Two weeks later she reported that a singleapplication of the formulation completely relieved pain, itch, andeczema within five minutes, and lasted for 7 hours or longer. Six monthslater she reported that pain relief from a single application had lastedlonger and longer and that the ankle finally had become completelywithout pain for about three months. The foregoing results indicate thatformulations of creatine monohydrate applied topically have strongefficacy in clinical use for control of pain secondary to inflammation.

Example 9 Effect on Painful Swelling of Knee Joint

A 59 year old female subject with relentless painful swollen right kneefor 3-4 years, not relieved by oral ibuprofen, was tested and ratedanalgesic efficacy of the three following formulations applied topicallyto the knee.

Formulation C12-3:

Component Percentage (%) HCl salt of ethyl creatinate 3 Meglumine 3Water:ethanol:propylene 94 glycol = 4:3:3 Final pH 7.5

Rating: This formulation was rated lowest among the three testedformulations. Complete relief of pain, itch, and eczema occurred within5 minutes. Duration of relief was 6-8 hours. Three to four applicationsdaily were required for sustained pain relief.

Formulation C₁₅-1:

Component Percentage (%) N-acetyl ethyl creatinate 1 Water:propyleneglycol = 8:2 99 Final pH 5.2

Rating: This formulation was rated next best and very good. Completerelief of pain occurred within 2-3 minutes and lasted for more than 12hours.

Formulation C₁₅-2:

Component Percentage (%) N-acetyl ethyl creatinate 2 Water:propyleneglycol = 8:2 98 Final pH 5.3

Rating: This formulation was judged to be the best and outstanding.Complete relief of pain occurred within 2-3 minutes and lasted at leastfor 24 hours.

The foregoing results indicate that chemical derivatives of creatineapplied topically have very strong analgesic efficacy in clinical usefor control of pain in different disorders.

Example 10 Effect on Acute Knee Pain

A 43 year old female subject with painful left knee gave a history ofphysical trauma to the left knee while cleaning her house. Degree ofpain was sufficiently intense that it required her to wear a knee bracethroughout the day, daily. One week later she helped remove heavy snowfrom outside access ways, during which time she sustained a traumatictwisting of the knee that resulted in intensified pain of the knee. Thesubject was provided a formulation of N-acetyl ethyl creatinate 1.5%dissolved in water: propylene glycol 8:2 for topical application. Atfollow-up 5 days later she reported that within about 2 minutes afterapplication of the formulation to the knee, pain in the knee completelyvanished “like a miracle”. Pain had not recurred at the time of herreport 10 days later. These results indicate that a derivative ofcreatine of the present invention applied topically in clinical use hasvery strong efficacy against inflammation and concomitant pain secondaryto physical trauma of a joint.

Example 11 Effect on Acute Neck Pain

A 44 year old male subject who had shoveled heavy snow all day, throwingthe snow mostly to left, upon arising from bed the next morningexperienced acute pain in the left side of his neck that intensified ashe attempted to move his head in any direction. His spouse had in herpossession the formulation of N-acetyl ethyl creatine 1.5% dissolved inwater: propylene glycol 8:2 that she had topically used the previous dayto obliterate pain in her left knee as described in Example 10, whichformulation she applied to the neck of her husband. Within 2 minutes hisneck pain subsided completely and did not return.

This result affirms that a derivative of creatine of the presentinvention applied topically has very strong efficacy in clinical use forcontrol of pain secondary to muscle inflammation due to stress ofexcessive muscle use.

Example 12 Effect on Multiple Pain, Itch, Eczema Sites

The subject in this Example was a 59 old female with pain emerging inmultiple anatomic sites over the past decade. Current persistentdisabling pain, itch, eczema problems include lower back pain and painin the right hip. For both conditions she compared the pain relievingefficacy of the following two topically applied formulations.

Formulation 1:

Component Percentage (%) Creatine monohydrate 2.5 Sodium lauryl sulfate1.5% Mineral oil   1% Vehicle:water:glycerin:propylene glycol 5:2:3

Formulation 2 was:

Component Percentage (%) N-acetyl ethyl creatine 1.5Vehicle:water:propylene glycol 8:2

After topically testing for the efficacy of each formulation to relievelower back pain and hip pain, she reported that Formulation 1 relievedin both sites by an estimated degree of 75% that lasted for 2-3 hours,and that Formulation 2 relieved pain completely and lasted for 4-5hours.

These results indicate that creatine and derivative thereof appliedtopically can substantially relieve pain of inflammation of differentkinds. Such eradication of the symptom of pain that often occurs withinflammation, by creatine and related compounds introduces a newcategory of non-steroidal anti-inflammatory agents, as well as a newcategory of anti-pain agents, both of which can be viewed as havingpossible immense clinical use.

Example 13 Effect on Rheumatoid Arthritis Fingers

A 60 year old female subject noted changes in her fingers that appearedto be compatible with the diagnosis of early rheumatoid arthritis inautumn of the year. At about one month later there appeared over theterminal interphalangeal joint of the left third finger a raisedinflammatory nodule compatible with the diagnosis of a rheumatoidnodule. The nodule was injected with 0.15 ml of a 2% aqueoussolution/suspension of creatine monohydrate once weekly for fourinjections. Over a period of 9 weeks the nodule resolved almostcompletely, leaving a faint erythema at the site. Thereafter, for aperiod of one month, the subject wore a nitrile glove containing a fewdrops N-acetyl ethyl creatine 3% dissolved in water: propylene glycol8:2 for about an hour twice daily on the left hand only. After anothertwo months the following benefits had occurred:

-   -   The left hand was said to feel much better than the right hand;    -   The site of the nodule remained a slightly erythematous flat        macule;    -   The left hand and fingers were completely flexible; the        flexibility of the right hand was restricted; and    -   In making a tight fist of both hands, the size of the left fist        was visibly smaller than that of the right. In making the fists        the subject reported that the left fist was pain free whereas        the right fist was substantially painful.

The foregoing results indicate that creatine injected into a rheumatoidnodule can resolve the nodule and that a derivative of creatine appliedtopically is associated with improvements of the signs and symptoms ofrheumatoid arthritis. These events suggest that creatine and derivativesthereof can be viewed as having possible immense therapeutic benefit inclinical management of rheumatoid arthritis.

Example 14 Effects of Subcutaneous Injection of Creatine over Sites ofSpinal Pain

A physician subject, age 98, with continually worsening osteoarthritisof multiple joints for 15-16 years, prepared a sterile aqueousinjectable solution/suspension of 2% creatine monohydrate. Under hisdirection, medical assistants were instructed on techniques to givesubcutaneous injections of the 2% aqueous solution/suspension witheither a 1 ml syringe with 27 gauge 13 mm needle or with a 1 ml insulinsyringe with 30 gauge 8 mm needle.

Five intervertebral painful sites of arthritis of cervical and thoracicspine, identified by finger pressure, received a single injection of 0.3ml of the solution. All sites/areas became pain free within 2-3 hoursafter injection, and without receiving any further therapy, remainedpain free for 7 weeks.

The foregoing results indicate that creatine monohydrate and itssubcutaneous injections over sites of arthritic or arthritic-like pain,both of the present invention, are strongly beneficial in clinical useas treatment of spinal arthritis or analogous inflammatory conditions ofthe spine.

Example 15 Effects of Subcutaneous Injection of Creatine over Ankle withPsoriatic Arthritis

A diabetic female subject, age 61, with psoriasis for over 4 decades,and worsening psoriatic arthritis for about 10 years, presented with anacutely painful, swollen and erythematous right ankle. Using a 1 mlinsulin syringe with short needle she injected 0.5 ml of the 2% creatinemonohydrate as described above into a subcutaneous site of the anteriorankle. Ankle pain completely resolved within about 30 minutes. The edemaand erythema of the ankle completely resolved within a week. Four weeksafter the injection the ankle remained pain free, was of normalappearance, and was completely functional as a normal ankle.

The foregoing results indicate that creatine and its subcutaneousinjection over sites of inflammation and pain, both of the presentinvention, are strongly anti-inflammatory and relieve pain associatedwith such inflammation.

Example 16 Effects of Subcutaneous Injection of Creatine for Relief ofHip Pain

A female subject, age 59, who for several weeks was experiencingdisabling arthritic pain in the right hip joint, was given twosubcutaneous injections of a sterile 2% aqueous solution/suspension ofcreatine monohydrate over the point of pain, 0.5 ml given first, and 0.6ml given five days later. Complete relief of pain lasted for 2 weeksbefore a returning mild pain was sensed, which slowly worsened over thenext week. A third subcutaneous injection of 0.7 ml of the 2% creatinemonohydrate solution/suspension was given over the point of joint painelicited by finger pressure. Complete relieve of pain occurred within3-4 hours. Hip remained pain free for another 2 weeks.

The foregoing results indicate that creatine monohydrate and itssubcutaneous injection over a site of pain associated with inflammationare strongly analgesic in clinical use in relieving hip pain.

Example 17 Effects of Creatine for Post Dental Surgery Pain

A male subject, age 88, had three teeth, #23, 24 and 25 extracted at 12noon, then had two implants posted immediately after. At about 6 pm,subject started to feel pain in the gum area after lidocaine anesthesiawore off. Subject was instructed to use Stellalife^(R) antimicrobialmouth rinse several times, which however provided no pain relief. Thesubject took about 1 gram creatine monohydrate powder into mouth. Thepowder, as it dissolved in saliva, was rinsed for approximately 5minutes, then swallowed. The dental pain stopped in about 20 minutes,and relief lasted for 8 hours.

The above result shows that creatine can be effective in eradicatingdental pain on topical application to the gum area.

Example 18 Effect of Whole Body Application

A 98 year old male subject with continually worsening very painfulosteoarthritis of multiple joints for 15-16 years prepared the followingformulation:

N-Acetyl Ethyl Creatinate (C₁₅): Water: Propylene glycol: Mineral Oil:Sodium lauryl sulfate 68 : 30:0.5:1.5:38.

After taking a morning shower, the entire 40 ml formulation was appliedby himself and his assistants to his entire body, except the scalp.Within about 5 minutes all pain ceased in all previously painful joints,i.e., spine, right shoulder, right elbow, knees and feet. The subjectwas without any sense of pain for 4.5 hours when mild painful discomfortin the neck was sensed. Over the next 3 hours pain in all jointsreturned to usual substantial levels.

The foregoing results suggest that a sufficient amount of N-acethylethyl creatinate may have been absorbed percutaneously to provide asystemic effect.

Example 19 Effects of Abdominal Subcutaneous Injections

A 98 year old male physician subject with continually worsening, for15-16 years, painful osteoarthritis of numerous joints (almost entirespine, wrists, right shoulder, knees and most recently the feet) on oneday at 11:30 AM self injected subcutaneously the right abdominal areawith 3 ml of a sterile aqueous solution that he had prepared containingN-acetyl ethyl creatinate 1%, arginine 0.25%, pH 7. Using lml insulinsyringes with short 8 mm needles 1 ml of the solution was injected intoeach of 3 sites. Ten minutes later his whole body was 95+% pain free andremained so for 3.5 hours when pain was sensed to be returning. Pain inusual severity returned within another 20-30 minutes.

The next day at 9:00 AM the subject injected 5 sites, each with 1 ml ofthe same solution. Within 10 minutes his whole body again was 95+% painfree. This almost complete pain free state was maintained for 4 hourswhen very mild pain in the knees was sensed. Pain in knees and incervical spine returned to usual degree of severity within an ensuingperiod of about 20 minutes.

The foregoing results show that whole body pain relief of inflammatoryjoint pain of arthritis can be achieved by a creatine derivativeadministered subcutaneously.

Example 20 Rapid Pain Relief and Resolution of Aphthous Ulcers (CankerSores) by Topical Application of N-Acetyl Ethyl Creatinate (C₁₅)

Two eroded painful sites 2-3 mm in diameter on the right side of thetongue worsened over 2 days in a 98 year old male subject. At bedtime ofthe 2nd day, the subject topically applied C₁₅ ₃% in water: propyleneglycol 8:2. Complete pain relief occurred within less than a minute. Thesites remained pain free throughout the night and did not return. Noclinical sign of the lesions could be detected next day by subject, norby two associates. The foregoing experience suggests that topical C15can be efficacious in general routine therapy of canker sores.

Example 21 Subcutaneous Injection of N-Acetyl Ethyl Creatinate (C₁₅)over Bunion Leads to Gradual Resolution of the Deformity

A 50 year old female subject presented with bunion on right foot thathas been enlarging over the past decade. Weekly subcutaneous injectionsover the bunion of C15 1.5% in aqueous solution has revealed the bunionhas undergone a distinct resolution in mass. Weekly injections will becontinued for another month or two to determine whether completeresolution will be achieved.

Example 22 Instant Complete Relief of Pain of Thermal Burns by TopicalN-Acetyl Ethyl Creatinate (C₁₅)

One subject, a 62 year old male, spilled boiling hot water on his lefthand. Within a couple hours pain was intense. He then applied 4%solution of N-acetyl ethyl creatinate (C₁₅) dissolved in water: ethanol:propylene glycol 5:3:2 which he had been using to relieve pain over alateral meniscus. He reported there was immediate relief of the burnpain for periods of 4-5 hours. Such application was continued over thenext several days until the burn pain disappeared spontaneously.

A second subject, a 60 year old female, burned her forearm where sheaccidentally touched the hot oven rack. She immediately applied 9%solution of N-acetyl ethyl creatinate (C₁₅) dissolved in water: ethanol:propylene glycol 5:3:2 that she was using for topical treatment of herrheumatoid arthritis. Burn pain was completely instantly relieved,lasting for 4-5 hours. Repeated application were applied over the next 3days, until the burn pain spontaneously ceased.

These results indicate that topical applications of C15 could be used toroutinely relieve burn pain.

Example 23 Pain of Dystonia Relieved by Local Subcutaneous Injections ofN-Acetyl Ethyl Creatinate (C₁₅), Relief Lasting for 2-3 Weeks

A 59 year old female subject presented with muscular pain of her upperright back which had been diagnosed by neurologist as a symptom ofdystonia (which also caused involuntary tic movements of her head). Fivesites of the upper back were injected with 0.3 ml C15 in aqueoussolution using insulin syringes with 30G short needles. Complete reliefof pain occurred within the next hour, and such relief lasting for 2weeks. At that time the injections were repeated just before shedeparted on a trip to Europe. By phone she reported that relief of painwas lasting beyond two week period.

Example 24 Effects of N-Acetyl Ethyl Creatinate (C₁₅) on Osteoarthritisof Various Body Joints Elbow:

A 65 year old male subject presented with a history of painful rightelbow for several weeks. He was provided with a topical solution of C158% in WP 82. He has reported that application of this solution to theelbow relieved pain instantaneously completely lasting for 5-6 hours.

A 99 year old male subject with a history of right elbow for severalmonths applied the above same solution to the elbo

w multiple times. No pain relieve was experienced.

On three other occasions, C15 1.5% aqueous solution 1 ml was injectedsubcutaneously in two lateral sites of the elbow and one site overextensor part of the elbow. Such injections provided complete relief ofpain within an hour, lasting for 24-30 hours.

Shoulder:

The same 99 year old male subject above has had painful right shoulderfor several months. Subcutaneous injections of 1 ml of the abovesolution on three occasions have provided complete relief of painlasting for 6-7 days.

Spine:

The same 99 year old subject above topically applied an adhesivedressing, 5 cm wide and 30 cm long, saturated with a solution of C15 4%in WP 82 to the upper spine. This provided complete relief of painwithin an hour, lasting for about 8 hours when the dressing was removedand found to be dry.

Over a period of 3 months, subcutaneous injections of 0.6 ml of theabove C15 solution were injected subcutaneously into each of 5intervertebral sites of the cervical and thoracic spine. On each of fiveoccasions complete relief of pain lasting for 1-4 weeks, wasexperienced.

Knees:

The 65 year old male subject described above has reported that asolution of C15, 8% in WP 82 applied to a gauze wrapping of the kneesand occluded with a plastic wrap has provided complete relief of painfor 8 hours of sleep. After removal in the morning he found that 85-90%diminishment of pain lasted for 7-8 hours. Several days later, arepeated application of the same procedure gave the same results.

The same 99 year old subject above, with severe osteoarthritis of theknees for 8-10 years, has found that topical application of C15, 8% inWP 82, even with occlusion provides only 3-4 hours of pain relief.

Example 25 Complete Pain Relief of Psoriatic Arthritis by TopicalN-Acetyl Ethyl Creatinate (C₁₅)

A 61 year old female subject with a 42 year history of psoriasis, andpsoriatic arthritis for the past 8 years, was provided a topicalsolution of C15 4% in WP 82. Application of the solution to painfuljoints of the wrists, hands, fingers and ankles provided almostinstantaneous, complete relief of pain that lasted for 6-24 hours. Thesubject has used topical formulations of C15 for over 12 weeks,comparing efficacy of 2%, 3.5% and 5% concentrations of C15. She hasfound that the most effective of the three has been 5% administered as aspray mist which has repeatedly provided complete pain relief for 24hours.

These results suggests that topical application of C15 could be used asa routine clinical treatment of psoriatic arthritis pain.

Example 26 Relief and Resolution of Pain and Joint Deformities ofRheumatoid Arthritis (RA) by Topical and Intralesional Injection of C15

A 60 year old female subject, described in an earlier Example, afterapproximately 4 months of worsening symptoms, and finger jointenlargements on both hands, realized that she was rapidly developing RA,especially when a rheumatoid nodule enlarged over the terminal joint ofthe left forth finger to a size of approximately 1 cm in diameter, andabout 3 mm thick. The nodule was initially injected with 0.15 ml of a 2%aqueous solution/suspension of creatine monohydrate once weekly for 4injections. Over a period of 9 weeks the nodule resolved almostcompletely. Thereafter the subject wore a nitrile glove containing a fewdrops of C15 3-9% dissolved in WP 82 for an hour twice daily on the lefthand only. After another 2 months C15 9% in WP 82 was topically appliedby means of her wearing nitrile gloves containing the C15 solution for 1hour twice daily. After 9 months of foregoing treatments both handsappear to be completely normal. It is intended for the subject tocontinue topical treatment in one form or another for an indefinite timeforward.

Example 27 Ankle Sprain Pain Completely Relieved with Topical N-AcetylEthyl Creatinate (C₁₅)

A 58 year old, female subject sprained her left ankle while hiking. Uponreturning home she was provided with a solution of C15 4% dissolved inWP 82 which she applied to the ankle 2-3 times daily for 4-5 days, atthe end of which time no ankle pain was detected and treatment wasdiscontinued.

Example 28 Mosquito Bite Itch Completely Eradicated by Topical N-AcetylEthyl Creatinate (C₁₅)

Six subjects, 2 males and 4 females, age 31-74 years, who had gatheredfor a back yard cookout, suffered multiple mosquito bites. One subjectcarried with her 2 ounces of C15 6% in WEP 532 which she shared with thefive others for topical application to the pruritic urticarial mosquitobite lesions. All six subjects claimed that the itch was completelyeradicated within about 1 minute. No itch returned.

Another subject, a 36 year old female, who had a history of being verysensitive to mosquito bites, was provided a solution of C15 6% in WEP532 to be topically applied to sites of mosquito bite reactions. Thissolution was later applied to an intensely pruritic urticarial lesion, 1cm in diameter, due to a mosquito bite. Within 1 minute of applicationall itch sensation was gone and did not return. Clinical evidence of thelesion began to fade about 3 minutes later, and at 5 minutes the subjecthad no sensory awareness of the lesion as it disappeared over the next10-15 minutes.

The foregoing results indicate that C15 applied topically istherapeutically efficacious in eradicating itch associated withinflammation as occurring in the reaction to mosquito bites.

Example 29 Relief of Migraine Headache by Topical N-Acetyl EthylCreatinate (C₁₅)

A 60 year old female subject, with a history of migraine headaches andassociated symptoms, presented with a recurrent episode of such that hadbegun during her night of sleep. Symptoms included an intense frontalheadache, and feeling of light dizziness, and nausea when she turned herhead. She was provided a 9% solution of C15 dissolved in WEP 532 to beapplied to the forehead and temporal areas as needed to relievesymptoms. Applications relieved symptoms within a few minutes. Relieflasted for 1-4 hours during the first day of use, and during the secondday of use, the subject experienced a much longer period of relief ofsymptoms. On the morning of the third day, symptoms were very mild; andat the end of the day, following 3 more applications, symptoms were nolonger detectable. She remained symptoms free over the next week offollow-up. The foregoing results show that symptoms of migraine can berelieved with repeated topical applications of N-acetyl ethylcreatinate, and can be completely eradicated after 2 days of use.

Example 30 Relief of Itch, and Improvement of Eczema by Topical N-AcetylEthyl Creatinate (C₁₅)

A 31 year old male subject, with a 25 year history of eczema, wasprovided a topical formulation of 6% C15 in a lotion made up ofhydrophilic ointment USP 35% diluted with 65% water. After ten days oftopical application that relieved the itch for intervals of 1.5 hour upto 24 hours, the subject felt his eczema was undergoing resolution. Heemphasized, however, that his eczema worsens in the autumn and winter,so his final judgment needs to be delayed from the summer season toseveral months later.

A 19 year old female subject with a 14 year history of eczema wasprovided the same lotion. After 2 weeks of applying the lotiontopically, she has reported that itch was relieved completely for 24-48hours following a single application.

A 40 year old female subject, with a history of eczema for 35 years, wasprovided the same solution. After 4 days of application to relieve itchas needed, she reported that itch was now negligible and that her skinwas nearly entirely free of signs of eczema. She has expressed greatgratitude and hopes that the same beneficial results will persist duringthe autumn and winter seasons.

The foregoing results indicate that topical N-acetyl ethyl creatinatecan provide substantial improvement of physical signs of eczema, and cancompletely relieve itch associated with the disorder.

Example 31 Instantaneous Complete Relief of Sore Throat by Spray Mist ofAqueous N-Acetyl Creatinate (C₁₅)

A 59 year old female subject, upon arising from bed in the morning, wasacutely aware of a severe sore throat. Clinical examination about 4hours later revealed her to have a deeply erythematous pharyngitishaving no signs of bacterial infection. She was provided, in a 2 ozspray container, a 3% aqueous solution of C15 that she sprayed into hermoth toward the inflamed pharynx. She reported an immediate completerelief of pain, which lasted for 25 minutes. Repeated spraying duringthe day were followed by longer pain free intervals. She reported thatat 7 PM the last pain free interval had been 1 hour. Next morning thepharyngitis had improved, and the subject used spray mist lessfrequently.

The foregoing results indicate that C15 solution spray can be usedclinically to relieve painful pharyngitis.

Example 32 Complete Relief of Itch of Dermatitis of Uncertain Etiologyby Topical N-Acetyl Ethyl Creatinate (C₁₅)

A 36 year old female subject who had worked planting a new rock andflower garden during the day, in the evening became acutely aware of anitch sensation in the lower back, just below the beltline. A photo ofthis area revealed it to be diffusely erythematous with scatterednumerous punctate sites more intensely erythematous. Itch was completelyrelived by topical application of C₁₅ ₄% in water: propylene glycol 8:2that had been provided to her earlier. Itch relief lasted for 2-3 hours;three additional applications were made during the night. The dermatitisand itch resolved early next day. Etiology was not ascertained.

The above experience indicates that topical application of C15 relievesinflammatory itch.

Example 33 Relief of Post Trauma Pain by Topical N-Acetyl EthylCreatinate (C₁₅)

A 65 year old subject was provided a 9% solution of C15 in WEP 532 forpossible use against itch or pain. Several weeks later she sent bye-mail the following message:

“Yesterday I slammed the top of my hand accidentally against a door.That really hurt and I could barely move my hand. Started to ice it andthen realized that I had decided to keep one bottle of the pain medicinehere at the shore. Put the med on it and in a minute or two the painwent away. Like a miracle. Iced it after as I could tell a welt wasforming. Again at bedtime I put a little of the pain med on it in casethe earlier application wore off and iced again as it was a bit swollen.Looked red and maybe a little swollen this morning but no pain!”

The foregoing case account affirms the clinical value of C15, in aformulation to have on hand for emergency use.

Example 34 Complete Relief of Ankle Pain Five Months after SurgicalInsertion of 10 Metal Screws into Fractured Bones by TopicalN-2-acetoxybenzoyl ethyl Creatinate (C₂₆)

A 45 year old male subject with above described post trauma pain at theend of each day experienced painful discomfort in the pinned ankle.Prior applications of C15 formulations provided substantially relievethe pain but not completely. Application of a liquid formulation,vehicle of which was WEP 244, 6% C₂₆ completely relieved the pain within1 minute. Complete relief lasted nearly 24 hours.

At the end of the next day, the ankle was as painful as the days before.Subject applied 6% C₂₀ in same liquid vehicle. Some relief did occur butnot complete as with C₂₆. The foregoing results indicate that compoundsof the present invention can be applied clinically to relive pain ofdifferent kinds.

Example 35 Complete Relief of Pain of Psoriatic Arthritis by TopicalApplication of N-benzoyl ethyl Creatinate (C₂₀) and byN-2-acetoxybenzoyl ethyl Creatinate (C₂₆)

A 60 year female subject with a 40 year history of psoriasis and severalyears of psoriatic arthritis topically applied the formulations cited inExample 34 above. Formulation of C20 was applied to both hands. Thesubstantial pain of fingers, hands and wrists was completely relievedwithin about 2 minutes and lasted for 4 hours. The formulation of C26was applied to the left ankle and foot, pain of which was relieved inabout 5 minutes and lasted for 4-5 hours.

The foregoing results indicate that C₂₀ and C₂₆ solutions can betopically used clinically.

Example 36 Poison Ivy Dermatitis Itch Instantly and Completely Relievedby Topical

Application of N-Acetyl Ethyl Creatinate (C₁₅) and Dermatitis Resolvedwithin Four Days

A 55 year old male subject developed poison ivy dermatitis of hisforearms about 18 hours after pruning bushes. Itch was intense at 24hours when he applied C₁₅ ₁₀% in a lotion made up of hydrophilicointment USP 35% diluted with 65% water. Relief of itch was immediate,lasting for about 6 hours when C15 was again applied. Duration of itchrelief next was for about 10 hours and the next for 12-15 hours. Reliefwas longer and longer from subsequent applications. Signs and symptomsof dermatitis were gone at 4 days.

The foregoing results indicate that C15 can be clinically used topicallyfor treatment of poison ivy dermatitis.

Example 37 Relief of Itch, and Improvement of Eczema by Topical N-AcetylEthyl Creatinate (C₁₅)

A 31 year old male subject, with a 25 year history of eczema, wasprovided a topical formulation of 6% C15 in a lotion made up ofhydrophilic ointment USP 35% diluted with 65% water. After ten days oftopical applications, itch was relieved for intervals of 1.5 hour up to24 hours. The patient felt that his eczema was undergoing resolutionduring the summer. At the end of the following February, he reportedthat his eczema was still under almost complete resolution. Sites ofitch were treated with prompt application of the above lotion whichcompletely aborted further development.

A 19 year old female subject with a 14 year history of eczema wasprovided the same lotion. After 2 weeks of applying the lotiontopically, she has reported that itch was relieved completely for 24-48hours following single applications. Patient has moved from the area andhas been lost to long term follow up.

A 40 year old female subject, with a history of eczema for 35 years, wasprovided the same formulation. After 4 days of application to relieveitch as needed, she reported that itch became negligible. Withapplications as needed her skin became nearly entirely free of signs ofeczema. She expressed great gratitude and hoped that the same beneficialresults would persist during the autumn and winter months. At the end ofFebruary she has reported that her skin has remained clear.

She reported: “I use it sparingly. If I feel any itch or see a littlepatch I put it on and it's gone like the next day. When it was hot andcold last week I would put a little on at night just in case and I neverhad an issue. It's so great. It's miraculous!”

The foregoing results indicate that C15 can be clinically used topicallyfor treatment of eczema.

Example 38 Burning Itch Induced by Mucuna Pruriens Completely Relievedby Topical N-acetyl ethyl Creatinate (C₁₅)

Pods with beans were obtained from Afro Caribe Botanica, 16 separatespecimens. Small round brushes marketed for interdental cleaning wereused to collect spicules from the pods. Application to both volar andextensor surfaces of the forearm were made by intense rubbing of theskin with such brush containing spicules. Burning itch developed within5-7 minutes. Topical application of C15 10% in a lotion made up ofhydrophilic ointment USP 35% diluted with 65% water gave complete reliefof itch within 1-2 minutes and was permanent. Participants in this studyincluded the following;

1. A 99 year old male.

2. A 65 year old male.

3. A 45 year old male.

4. A 61 year old female.

5. A 44 year old female.

The foregoing results indicate that C15 can be clinically used topicallyfor treatment of most intensive burning itch.

1. A method for treating pain in a human subject in need thereof, themethod comprising administering to the human subject a compositioncomprising a creatine derivative of Formula (2):H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2) or a pharmaceutically acceptablesalt thereof or a solvate thereof, and optionally a pharmaceutically orcosmetically acceptable carrier, wherein, R₁ is H or an acyl radicalhaving up to 29 carbon atoms; R₂ is H, OR₃, NHR₄, or any other aminogroup containing radical having up to 10 carbon atoms; R₃ is H, analkyl, aralkyl or aryl radical, wherein the alkyl, aralkyl or arylradical has up to 19 carbon atoms; and R₄ is H, OH, an alkyl, aralkyl,aryl or acyl radical, wherein the alkyl, arakyl, aryl or acyl radicalhas up to 19 carbon atoms, with a proviso that R₂ is not OH when R₁ isH.
 2. The method of claim 1, wherein R₁ is H or an acyl radical havingup to 19 carbon atoms, and the acyl radical is selected from the groupconsisting of acetyl, butanoyl, benzyloxycarbonyl, benzoyl, formyl,hexadecanoyl, hexanoyl, heptanoyl, linoleic, linolenic, nonanoyl,octanoyl, propanoyl, phenylacetyl, pentanoyl, and pyroglutamyl.
 3. Themethod of claim 1, wherein R₂ is H, OH, OEt, OC₃H₇, NHOH, or NH₂.
 4. Themethod of claim 1, wherein R₂ is NHNH₂, NHNHAc, NHCONH₂, NH(C═NH)NH₂,NH(C═NH)NHNH₂, NHNH(C═NH)NH₂, NH(C═NH)NHNHAc, NHNH(C═NH)NHAc, or(H₃C)₂N(C═N)N(CH₃).
 5. The method of claim 1, wherein the creatinederivative is selected from the group consisting of:H₂NC(═NH)N(CH₃)CH₂CONH₂, H₂NC(═NH)N(CH₃)CH₂COOC₂H₅, H₂NC(═NAc)N(CH₃)CH₂COOH, H₂ NC(═NAc)N(CH₃)CH₂CONH₂,H₂NC(═NAc)N(CH₃)CH₂COOC₂H₅, H₂NC(═NH)N(CH₃)CH₂CHO,H₂NC(═NAc)N(CH₃)CH₂CHO, H₂ NC(═NBz)N(CH₃)CH₂COOH, H₂NC(═NBz)N(CH₃)CH₂CONH₂, H₂NC(═NBz)N(CH₃)CH₂COOC₂H₅,H₂NC(═NBz)N(CH₃)CH₂CHO, H₂NC(═NH)N(CH₃)CH₂CONH(C═NH)NH₂,H₂NC(═NAc)N(CH₃)CH₂CONH(C═NH)NH₂, H₂NC(═NH)N(CH₃)CH₂CONHNH(C═NH)NH₂H₂NC(═NAc)N(CH₃)CH₂CONHNH(C═NH)NH₂, H₂NC(═NAb)N(CH₃)CH₂COOC₂H₅,H₂NC(═NAb)N(CH₃)CH₂COOH, H₂NC(═NAb)N(CH₃)CH₂CONH₂,H₂NC(═NAc)N(CH₃)CH₂COOC₃H₇, H₂NC(═NAb)N(CH₃)CH₂COOC₃H₇, andH₂NC(═NPc)N(CH₃)CH₂COOH. 6.-8. (canceled)
 9. The method of claim 1,wherein the composition comprises at least 1% by weight or volume, basedon a total weight or volume of the composition, of the creatinederivative of Formula (2) or a pharmaceutically acceptable salt thereofor a solvate thereof.
 10. (canceled)
 11. The method of claim 1, whereinthe composition is topically administered or systemically administered.12.-14. (canceled)
 15. The method of claim 1, wherein the method furthercomprises administering another pharmacological agent to providesynergetic or synergestic effect.
 16. (canceled)
 17. The method of claim1, wherein the pain is associated with a medical condition, disorder ordisease, and the medical condition, disorder or disease is selected fromthe group consisting of arthritis, headache, dental pain, eczema,lipoma, muscle pain, pharyngitis, sprain, trauma, sunburn, mosquitobite, and thermal burns. 18.-19. (canceled)
 20. A method for treatingitch in a human subject in need thereof, the method comprisingadministering to the human subject a composition comprising a creatinederivative of Formula (2):H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2) or a pharmaceutically acceptablesalt thereof or a solvate thereof, and optionally a pharmaceutically orcosmetically acceptable carrier, wherein, R₁ is H or an acyl radicalhaving up to 29 carbon atoms; R₂ is H, OR₃, NHR₄, or any other aminogroup containing radical having up to 10 carbon atoms; R₃ is H, analkyl, aralkyl or aryl radical, wherein the alkyl, aralkyl or arylradical has up to 19 carbon atoms; and R₄ is H, OH, an alkyl, aralkyl,aryl or acyl radical, wherein the alkyl, arakyl, aryl or acyl radicalhas up to 19 carbon atoms, with a proviso that R₂ is not OH when R₁ isH.
 21. The method of claim 20, wherein R₁ is H or an acyl radical havingup to 19 carbon atoms, and the acyl radical is selected from the groupconsisting of acetyl, butanoyl, benzyloxycarbonyl, benzoyl, formyl,hexadecanoyl, hexanoyl, heptanoyl, linoleic, linolenic, nonanoyl,octanoyl, propanoyl, phenylacetyl, pentanoyl, and pyroglutamyl.
 22. Themethod of claim 20, wherein R₂ is H, OH, OEt, OC₃H₇, NHOH, or NH₂. 23.The method of claim 20, wherein R₂ is NHNH₂, NHNHAc, NHCONH₂,NH(C═NH)NH₂, NH(C═NH)NHNH₂, NHNH(C═NH)NH₂, NH(C═NH)NHNHAc,NHNH(C═NH)NHAc, or (H₃C)₂N(C═N)N(CH₃).
 24. The method of claim 20,wherein the creatine derivative is selected from the group consistingof: H₂NC(═NH)N(CH₃)CH₂CONH₂, H₂NC(═NH)N(CH₃)CH₂COOC₂H₅, H₂NC(═NAc)N(CH₃)CH₂COOH, H₂ NC(═NAc)N(CH₃)CH₂CONH₂,H₂NC(═NAc)N(CH₃)CH₂COOC₂H₅, H₂NC(═NH)N(CH₃)CH₂CHO,H₂NC(═NAc)N(CH₃)CH₂CHO, H₂ NC(═NBz)N(CH₃)CH₂COOH, H₂NC(═NBz)N(CH₃)CH₂CONH₂, H₂NC(═NBz)N(CH₃)CH₂COOC₂H₅,H₂NC(═NBz)N(CH₃)CH₂CHO, H₂NC(═NH)N(CH₃)CH₂CONH(C═NH)NH₂,H₂NC(═NAc)N(CH₃)CH₂CONH(C═NH)NH₂, H₂NC(═NH)N(CH₃)CH₂CONHNH(C═NH)NH₂H₂NC(═NAc)N(CH₃)CH₂CONHNH(C═NH)NH₂, H₂NC(═NAb)N(CH₃)CH₂COOC₂H₅,H₂NC(═NAb)N(CH₃)CH₂COOH, H₂NC(═NAb)N(CH₃)CH₂CONH₂,H₂NC(═NAc)N(CH₃)CH₂COOC₃H₇, H₂NC(═NAb)N(CH₃)CH₂COOC₃H₇, andH₂NC(═NPc)N(CH₃)CH₂COOH.
 25. The method of claim 20, wherein thecomposition comprises at least 1% by weight or volume, based on a totalweight or volume of the composition, of the creatine derivative ofFormula (2) or a pharmaceutically acceptable salt thereof or a solvatethereof.
 26. The method of claim 20, wherein the composition istopically administered or systemically administered.
 27. The method ofclaim 20, wherein the method further comprises administering anotherpharmacological agent to provide synergetic or synergestic effect. 28.The method of claim 20, wherein the itch is associated with a medicalcondition, disorder or disease, and the medical condition, disorder ordisease is selected from the group consisting of eczema, sunburn,mosquito bite, and dermatitis.
 29. A composition for topicaladministration to treat treating pain or itch or eczema in a humansubject in need thereof, the composition comprising a creatinederivative of Formula (2):H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2) , and optionally apharmaceutically or cosmetically acceptable carrier, wherein, R₁ is anacyl radical having up to 29 carbon atoms; R₂ is H or OR₃; R₃ is H, analkyl, aralkyl or aryl radical, wherein the alkyl, aralkyl or arylradical has up to 19 carbon atoms.
 30. The composition of claim 29,wherein the creatine derivative is selected from the group consistingof: H₂NC(═NAc)N(CH₃)CH₂COOC₂H₅, H₂ NC(═NAc)N(CH₃)CH₂COOCH₃, H₂NC(═NAc)N(CH₃)CH₂COOCH(CH₃)₂, H₂NC(═NAc)N(CH)CH₂COOC₃H₇,H₂NC(═NAc)N(CH₃)CH₂CHO, H₂NC(═NBz)N(CH₃)CH₂COOC₂H₅,H₂NC(═NBz)N(CH)CH₂COOCH₃, H₂ NC(═NBz)N(CH₃)CH₂COOCH(CH₃)₂, H₂NC(═NBz)N(CH₃)CH₂COOC 3H₇, H₂NC(═NBz)N(CH₃)CH₂CHO,H₂NC(═NAb)N(CH₃)CH₂COOC₂H₅, H₂NC(═NAb)N(CH₃)CH₂COOCH₃,H₂NC(═NAb)N(CH₃)CH₂COOCH(CH₃)₂, H₂NC(═NAb)N(CH)CH₂CHO,H₂NC(═NAb)N(CH₃)CH₂COOC₃H₇, H₂NC(═NPc)N(CH₃)CH₂CHO,H₂NC(═NPc)N(CH)CH₂COOCH₃ H₂NC(═NPc)N(CH₃)CH₂COOC₂H₅,H₂NC(═NPc)N(CH₃)CH₂COOC₃H₇, H₂ NC(═NPc)N(CH₃)CH₂COOCH(CH₃)₂H₂NC(═NFm)N(CH₃)CH₂COOC₂H₅, H₂ NC(═NFm)N(CH₃)CH₂COOCH₃ H₂NC(═NFm)N(CH)CH₂COOCH(CH₃)₂ H₂NC(═NFm)N(CH₃)CH₂COOC₃H₇, andH₂NC(═NFm)N(CH₃)CH₂CHO.
 31. A composition for cutaneous injection totreat pain or itch or eczema in a human subject in need thereof, thecomposition comprising a creatine derivative of Formula (2):H₂NC(═NR₁)N(CH₃)CH₂COR₂   Formula (2) optionally a pharmaceutically orcosmetically acceptable carrier, wherein, R₁ is an acyl radical havingup to 29 carbon atoms; R₂ is H, OR_(3;) R₃ is H, an alkyl, aralkyl oraryl radical, wherein the alkyl, aralkyl or aryl radical has up to 19carbon atoms;
 32. The composition of claim 31, wherein the creatinederivative is selected from the group consisting of:H₂NC(═NAc)N(CH₃)CH₂COOC₂H₅, H₂ NC(═NAc)N(CH₃)CH₂COOCH₃ H₂NC(═NAc)N(CH₃)CH₂COOCH(CH₃)₂ H₂NC(═NAc)N(CH₃)CH₂COOC₃H₇H₂NC(═NAc)N(CH₃)CH₂CHO H₂NC(═NBz)N(CH₃)CH₂COOC₂H₅,H₂NC(═NBz)N(CH₃)CH₂COOCH₃ H₂NC(═NBz)N(CH₃)CH₂COOCH(CH₃)₂H₂NC(═NBz)N(CH₃)CH₂COOC₃H₇ H₂NC(═NBz)N(CH₃)CH₂CHO H₂NC(═NAb)N(CH₃)CH₂COOCH₃ H₂ NC(═NAb)N(CH₃)CH₂COOCH(CH₃)₂H₂NC(═NAb)N(CH₃)CH₂COOC₃H₇ H₂NC(═NAb)N(CH₃)CH₂CHOH₂NC(═NAb)N(CH₃)CH₂COOC₂ H₅ H₂NC(═NPc)N(CH₃)CH₂CHO,H₂NC(═NPc)N(CH₃)CH₂COOCH₃ H₂NC(═NPc)N(CH₃)CH₂COOC₂H₅,H₂NC(═NPc)N(CH₃)CH₂COOC₃H₇, H₂NC(═NPc)N(CH₃)CH₂COOCH(CH₃)₂H₂NC(═NFm)N(CH₃)CH₂COOC₂H₅, H₂NC(═NFm)N(CH₃)CH₂COOCH₃H₂NC(═NFm)N(CH₃)CH₂COOCH(CH₃)₂ H₂NC(═NFm)N(CH₃)CH₂COOC₃H₇H₂NC(═NFm)N(CH₃)CH₂CHO